Temperature in humans is controlled by the hypothalamus around a set point of about 37 °C (98.6 °F), by a complex series of mechanisms that permit the generation, conservation, and dissipation of heat.

Homeothermy requires a balance of heat generation, heat conservation, and heat dissipation. This is accomplished by a remarkable series of coordinated cardiovascular and metabolic responses integrated in the hypothalamus, and fine tuned in the effector organs peripherally. These responses involve the autonomic nervous system, the skeletal musculature, arteries and veins, the sweat glands, and brown adipose tissue (BAT).

FEVER AND HYPERTHERMIA

Fever represents a resetting of the temperature set point up; antipyretics adjust the set point down when the latter is elevated by fever.

Fever is distinct from hyperthermia.

In hyperthermia the core temperature rises because heat dissipation mechanisms are impaired, or because heat production exceeds the capacity of heat dissipation mechanisms, not because of an increase in central temperature set point.

Infections cause fever via cytokine release from inflammatory cells.

In fact, the first cytokine described was called “endogenous pyrogen” since it was released from host leukocytes after exposure to bacteria. It had previously been thought that bacterial products per se caused the fever. Cytokines released from tumor cells also cause the fever that is associated with malignancy.

THERMOGENESIS

Thermogenesis, literally heat production, is not synonymous with fever.

In warm-blooded mammals (homeotherms) basal heat production (or basal metabolic rate [BMR]) is the heat produced at rest by mitochondria throughout the body. BMR is regulated by thyroid hormones.

Excessive sweating is the clinical manifestation of increased heat production without a rise in temperature.

In hyperthyroidism BMR is increased (thermogenesis), but fever is absent unless the increased heat production overwhelms the heat dissipation mechanisms.

HEAT GENERATION AND DISSIPATION

Heat dissipation mechanisms include sweating and vasodilation.

Vasodilation results in the loss of heat through the skin by radiation; sweating cools via evaporative heat loss. The latter is regulated by cholinergic sympathetic nerves to the sweat glands.

A rise in temperature of 1 °C results in a 10% to 13% increase in metabolic rate, contributing to the weight loss noted during prolonged febrile illness.

Maintenance of normal body temperature in spite of differing ambient conditions (homeothermy, the “warm blooded” state) consumes a significant amount of total energy production (about 50% in normally active man).

Rigors reflect the rapidity of a rise in temperature; they are not specific for any particular cause of the fever.

Heat generation occurs by the muscular activity induced by shivering; as the temperature rises during febrile illness episodes of shivering are experienced as rigors. It is a faux pearl that rigors are caused principally by gram-negative bacterial infections.

BAT is a heat-generating organ.

Although the role for BAT in physiologic heat production in small mammals and human neonates has been well accepted, BAT was long dismissed as irrelevant in adult humans. BAT has now been resuscitated and is generally recognized as functional in many adults. It is a faux pearl that BAT is neither present nor functional in older humans. A potential role for BAT (or lack thereof) in the pathogenesis of obesity is under investigation.

The production of metabolic heat in BAT is regulated by the sympathetic nervous system which turns on BAT metabolism by a β-3 receptor-mediated process. In the presence of uncoupling protein (UCP), BAT mitochondria become uncoupled so that substrate oxidation results in the production of heat rather than the synthesis of ATP. The location of BAT around the great vessels in the thorax facilitates distribution of the generated heat throughout the body. Heat production in BAT is markedly enhanced by chronic cold exposure, a process known as cold acclimation; in the cold acclimated state metabolic heat replaces the need to shiver during cold exposure.

In humans the extremities play an important role in temperature regulation.

Heat conservation occurs via vasoconstriction of arteries and superficial veins in the extremities. Venoconstriction, particularly in the superficial veins of the extremities, is mediated by α-2 adrenergic receptors, while the deep veins, which form a plexus around the arteries in the extremities, are more heavily endowed with α-1 receptors. External cooling decreases α-1 receptor affinity for NE in deep veins but increases α-2 affinity in the superficial veins, favoring a shift of blood to the deep venous system. The deep veins form a plexus around the arteries that supply the extremities, thus providing the anatomic basis for a countercurrent heat exchange mechanism. These vascular changes efficiently return heat from the arterial system perfusing the extremities to the central vascular compartment. The opposite vascular changes potentiate heat dissipation in a warm environment or when exercise necessitates heat loss.

When prescribing antipyretics it is preferable to dose the drugs at a regular interval rather than PRN for a rise in temperature, in order to avoid repeated heat generation and diaphoresis as the antipyretic wears off and is readministered.

During a febrile response heat is both conserved and generated, thereby raising the core temperature. Paradoxically, the patient feels cold since the core temperature is below the new (febrile) set point. When the fever breaks, either through resolution of the infection or the administration of antipyretics, heat is dissipated by vasodilation and sweating; the patient, paradoxically, feels warm, the core temperature now being above the normal set point.

DIURNAL VARIATION IN TEMPERATURE

Typically, fever peaks in the evening and diminishes in the morning, constituting a single daily spike.

Some diseases, however, are characterized by unusual fever patterns.

In Adult Still’s disease (juvenile rheumatoid arthritis [JRA]) two daily spikes are common.

JRA is an important cause of undiagnosed febrile illness in adults. It is a difficult diagnosis to establish since the manifestations are nonspecific (arthralgias, fever, sore throat) and the characteristic rash is frustratingly evanescent. Inflammatory markers are typically very high (WBC, platelet count, ferritin level).

In malaria the classical pattern of every other day or every third day fever spike is not established early in the disease, so daily spikes are the rule at the time of presentation.

Patients returning from an indigenous area with high spiking fever, headache, and malaise should be suspected of having malaria, especially if they have not taken appropriate prophylaxis.

In patients with a prolonged febrile illness that defies diagnosis the cause is usually malignancy.

Hospitalized patients with undiagnosed fever despite repeated cultures and imaging will usually be found to have an occult malignancy rather than an occult infection.

NIGHT SWEATS

Why do febrile (and nonfebrile) patients sweat at night?

During sleep the core temperature falls almost 0.5 °C; to meet the lowered central set point, heat dissipation mechanisms are activated resulting in sweating and vasodilation.

Although the temperature is falling paradoxically the patient feels hot (since the actual temperature is above the lowered set point).

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